A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Anaesthesiology / Background and Objective There has been a recent resurgence of interest in vitamin D and its far-reaching effects in physiology and pathophysiology. Theatre personnel, and all indoor workers, should be cognisant of vitamin D deficiency as a real occupational hazard. Vitamin D deficiency is a global problem that has been studied extensively in colder climates and even been found in warmer climates. No research was identified among medical personnel in South Africa. The primary objective of this study was to describe serum 25-hydroxyvitamin D (25(OH)D) levels of anaesthetists. The secondary objective was to describe and compare factors influencing vitamin D levels in anaesthetists who are vitamin D insufficient to those who are not. These factors included: ethnicity, gender, body mass index (BMI), multivitamin use, calcium or vitamin D supplementation, sun exposure, vitamin D intake from diet alone, vitamin D intake from diet and supplementation and calcium intake (dairy). Methods Data was collected over a period of one month, in winter (mid-July to mid-August 2013). On the morning of sample collection anaesthetists agreeing to participate signed the informed consent (Appendix 2), prior to enrolment in the study. The anaesthetists then completed the questionnaire (Appendix 5). The following data was obtained from the questionnaire: age, gender, ethnic group, dietary supplementation, sun exposure, sunscreen use, BMI and diet. Each participant had 5 ml of blood collected in a standardised manner into a purple top ethylenediaminetetraacetic acid blood specimen tube. The processing of samples was done by qualified laboratory personnel using standard chemical pathology equipment and procedures. High Performance Liquid Chromatography was performed to determine 25(OH)D levels using a Shimadzu® Nexera X2 Ultra performance liquid chromatography system with a photodiode array detector (Shimadzu®, Japan). Results The median 25(OH)D was 43.8 nmol/l (IQR 26-76), with 51 of 89 (57.30 %) anaesthetists being vitamin D insufficient. There was a statistically significant association between ethnicity and vitamin D status (p<0.001). Twenty-one (80.77 %) Indian anaesthetists and 14 (70.00 %) black anaesthetists were vitamin D insufficient, as compared to only 10 (28.57%) white anaesthetists. There was no significant association between the other secondary objectives-gender (p=0.60), sun exposure (p = 0.93), vitamin D intake from diet alone (p= 0.07), vitamin D intake from diet and supplementation (p=0.05) and calcium intake (p=0.55) and vitamin D status. There was no significant difference between BMI and vitamin D status. When a comparison was made between the two groups of BMI <25 and BMI ≥25, using a Mann-Whitney test the two-tailed P value was 0.6791. There was a significant association between multivitamin use (p=0.01) and vitamin D status. Conclusion Vitamin D should no longer be a forgotten vitamin. The insufficient vitamin D levels of anaesthetist in this study, puts them at risk for pathology far beyond bone health. Adequate vitamin D levels should be seen as essential, rather than optional, even in “sunny” climates. / MT2016

Background: Determinants of vitamin D status are of interest when studying the epidemiology of disease in population groups because vitamin D is now recognized to decrease the risk of diseases such as osteoporosis, cancer, and cardiovascular disease. Understanding modifiable determinants of vitamin D status are important for managing vitamin D deficiency at the individual level and for addressing this issue at population level. Objective: The objective of this study was to evaluate the associations between serum vitamin D status (deficiency and insufficiency) and distinct demographic, dietary, and lifestyle characteristics of adults in the United States using a large, nationally representative sample survey, the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Methods: The study sample consisted of 2340 adults aged 20-59 who had serum 25(OH)D measured and who had completed various questionnaires concerning dietary intake of vitamin D and other lifestyle factors. Multivariate logistic regression was used to estimate the odds ratio (OR) of vitamin D deficiency, insufficiency, and sufficiency in adults based on distinct demographic, dietary, and lifestyle characteristics. Statistical significance was set at α < 0.05. Results: The prevalence of vitamin D deficiency was higher in obese adults than in underweight to normal weight adults (50.9% ± 4.57 vs. 29.3% ± 3.57), higher in adults who reported no sunburns than in adults who reported ≥ 3 sunburns (49.9% ± 3.82 vs. 18.0% ± 3.07), and higher in adults who use sun protective measures regularly than in adults who do not (48.4% ± 3.93 vs. 27.0% ± 3.75). The prevalence of vitamin D deficiency increased as dietary intake of vitamin D decreased. Non-Hispanic black adults were significantly more likely to be vitamin D deficient (OR = 45.27, 95% CI = 17.27-118.64) and insufficient (OR = 9.37, 95% CI = 3.43-25.61) than non-Hispanic white adults. Significant positive associations were found between vitamin D deficiency and several characteristics, namely obesity (OR = 7.43, 95% CI = 4.33-12.77), physical inactivity (OR = 1.63, 95% CI = 1.03-2.58) poor dietary vitamin D intake (OR = 2.34, 95% CI = 1.44-3.81), non-supplement use or supplement use with a low amount of vitamin D (OR = 1.75, 95% CI = 1.05-2.89), and activities that decrease exposure to sunlight (from OR = 2.97, 95% CI = 2.14-4.13 to OR = 5.30, 95% CI = 3.17-8.85). Conclusion: The results of this nationally representative study demonstrate that obesity, physical inactivity, poor dietary intake of vitamin D, and low sunlight exposure increases the risk for vitamin D deficiency in U.S adults. Future studies are needed to investigate whether vitamin D supplementation, sunlight exposure, and vitamin D-fortified foods are efficient in correcting vitamin D deficiency and insufficiency among these groups.

Background: Vitamin D may have beneficial effects on cardiometabolic disease, but the evidence is equivocal. This may be due to unaccounted confounders, such as lifestyle factors and genetic variation. We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] and biomarkers of cardiometabolic disease risk, including biomarkers of inflammation, glycemic dysregulation and lipid metabolism, and a panel of 54 plasma proteomic biomarkers, and determined whether lifestyle variables and genetic variation modified these associations. Methods: Participants were from the Toronto Nutrigenomics and Health Study, an ethnically diverse population of individuals aged 20-29 years. Anthropometric measurements were obtained. Participants answered general health and lifestyle and food frequency questionnaires and provided a fasting blood sample for biochemical measurements and genotyping. Results: Across ethnic groups, women who used hormonal contraceptives (HC) had higher 25(OH)D and C-reactive protein (CRP) than women HC non-users and men. Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use. However, there was no association after accounting for HC use. 25(OH)D was also not associated with inflammatory cytokines after adjusting for HC use. 25(OH)D was inversely associated with insulin, HOMA-IR, and HOMA-Beta among Caucasians and East Asians and among men and women HC non-users. No biomarkers were associated with 25(OH)D among South Asians and women HC users, although non-significant inverse trends were observed for markers of glycemic dysregulation. Only two of the 54 plasma proteomic biomarkers were associated with 25(OH)D in women HC non-users, and none were associated in men. Among women HC users, after accounting for hormone dose, only three proteins were associated with 25(OH)D. Finally, 25(OH)D affected the association between rs2239182, a variant in the vitamin D receptor (VDR) and the pro-inflammatory cytokine interferon gamma-induced protein 10 (IP-10). However, the association was suggestive of heterosis and may have been due to chance. Conclusions: We identified a confounding effect of HC use on the association between 25(OH)D, biomarkers of inflammation and plasma proteomic biomarkers. In addition, HC use might also affect the association between 25(OH)D and biomarkers of glycemic dysregulation. Genetic variation in VDR did not modify any associations.

Background: Vitamin D may have beneficial effects on cardiometabolic disease, but the evidence is equivocal. This may be due to unaccounted confounders, such as lifestyle factors and genetic variation. We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] and biomarkers of cardiometabolic disease risk, including biomarkers of inflammation, glycemic dysregulation and lipid metabolism, and a panel of 54 plasma proteomic biomarkers, and determined whether lifestyle variables and genetic variation modified these associations. Methods: Participants were from the Toronto Nutrigenomics and Health Study, an ethnically diverse population of individuals aged 20-29 years. Anthropometric measurements were obtained. Participants answered general health and lifestyle and food frequency questionnaires and provided a fasting blood sample for biochemical measurements and genotyping. Results: Across ethnic groups, women who used hormonal contraceptives (HC) had higher 25(OH)D and C-reactive protein (CRP) than women HC non-users and men. Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use. However, there was no association after accounting for HC use. 25(OH)D was also not associated with inflammatory cytokines after adjusting for HC use. 25(OH)D was inversely associated with insulin, HOMA-IR, and HOMA-Beta among Caucasians and East Asians and among men and women HC non-users. No biomarkers were associated with 25(OH)D among South Asians and women HC users, although non-significant inverse trends were observed for markers of glycemic dysregulation. Only two of the 54 plasma proteomic biomarkers were associated with 25(OH)D in women HC non-users, and none were associated in men. Among women HC users, after accounting for hormone dose, only three proteins were associated with 25(OH)D. Finally, 25(OH)D affected the association between rs2239182, a variant in the vitamin D receptor (VDR) and the pro-inflammatory cytokine interferon gamma-induced protein 10 (IP-10). However, the association was suggestive of heterosis and may have been due to chance. Conclusions: We identified a confounding effect of HC use on the association between 25(OH)D, biomarkers of inflammation and plasma proteomic biomarkers. In addition, HC use might also affect the association between 25(OH)D and biomarkers of glycemic dysregulation. Genetic variation in VDR did not modify any associations.

ANALYSIS OF PREVALENCE OF VITAMIN D DEFICIENCY IN ADULTS Author: Jana Nováková Supervisor: PharmDr. Eva Zimčíková, PhD. INTRODUCTION Estimated vitamin D deficiency occurs in up to 1/3 of the population. Vitamin D deficiency occurs in a number of diseases and in different countries of the world. AIMS The aim of the theoretical part of the diploma thesis was to get acquainted with vitamin D and its deficit in general. The objective of the practical part was to map vitamin D levels in adults, to assess prevalence of vitamin D deficiency, to determine if vitamin D levels fluctuate over the course of the year depending on age or gender and how they are related to individual illnesses. METHODS PubMed and Embase database search was performed to find evidence on vitamin D deficiency in adults. Only studies in humans, published in English in the period from 2000 to 2016 were included. Non-systematic review was provided, the quality of the studies was not evaluated. RESULTS Overall, 84 studies were included. Most of the studies enrolled healthy adults (n = 34). Among the studies concerning various diseases, musculoskeletal disorders were the most prevalent (n = 13). The highest prevalence of vitamin D deficiency was seen in the study from USA (in healthy adults) using cut-off value for deficiency ≤ 50...

Multiple sclerosis (MS) is a progressive, autoimmune neurodegenerative disorder affecting nearly 350,000 people in the United States and resulting in significant disability. As an immunomodulator, vitamin D may play a role in the development of MS. Previous studies have observed an inverse association of 25-hydroxyvitamin D (25(OH)D) levels and MS risk in younger populations; however, whether this relationship persists in older adults remains unclear. We prospectively investigated the association between predicted 25(OH)D level and incident MS in the Nurses’ Health Study (NHS) (n=121,701) and NHS II (n=116,430). 25(OH)D levels were predicted using validated regression models that include important determinants of vitamin D status, including race, UV-B flux (based on state of residence), physical activity, body mass index, dietary vitamin D intake, alcohol consumption and post-menopausal hormone use. Data on these factors were self-reported on NHS and NHS II questionnaires starting in 1986 and 1991, respectively, and updated every 2-4 years. MS diagnoses were ascertained by self-report and confirmed by medical records. Cox proportional hazards models adjusted for age, ethnicity, latitude of residence at age 15, and BMI at age 18 were used to estimate hazard ratios (HR)s and 95% confidence intervals (CI)s in each cohort. During up to 18 years of follow-up, we documented 179 definite/probable cases of MS with first symptoms after baseline. Multivariable HRs comparing highest and lowest quintiles of predicted 25(OH)D were 1.09 (95% CI: 0.40-2.96) in the NHS and 0.52 (95% CI: 0.28-0.95) in the NHS II. Higher predicted plasma 25(OH)D may be modestly associated with lower risk of MS, primarily in younger women.

Objectives: In recent years, vitamin D deficiency has been recognized increasingly often in patients, and different supplement regimens have been prescribed to treat it. There has been no consensus on treatment regimens. This study was conducted to determine the management of vitamin D deficiency/insufficiency in outpatient adults in northeast Tennessee. Methods: A retrospective record review was conducted in an internal medicine teaching clinic for patients seen from July 2007YJuly 2008 in Johnson City, Tennessee. A total of 626 nonelectronic charts listed with vitamin D measurements were used in the analysis. Data regarding the level of vitamin D, whether treatment was prescribed, dose and duration of treatment prescribed, and repeat levels of vitamin D, if any were ordered, were collected. Vitamin D deficiency was defined as levels G20 ng/mL; vitamin D insufficiency was defined as levels ranging from 20 to 29.9 ng/mL. Results: Of the 626 patients, 325 (52%) were vitamin D deficient or insufficient. Of these 325 patients, 184 were given a low-dose supplement and 54 received a high-dose supplement. Eighty-seven were either not prescribed any replacement or the dose was unknown (not documented in the chart). The mean change in serum vitamin D levels was significantly different for the high dose compared with the low dose prescribed. There was no significant sex difference in response to the dose given. On average, those who were vitamin D deficient experienced a greater change than those who were insufficient and a greater change, on average, was observed in those who received a higher dose. Conclusions: Vitamin D deficiency and insufficiency are highly prevalent. Clinicians tended to prescribe a high dose of treatment for lower levels of serum vitamin D. The response is higher in high-dose treatment. Documentation regarding whether vitamin D supplements were given or the dose of supplements was given and followed up with repeat levels of vitamin D after treatment was poor.

BACKGROUND:: Vitamin D deficiency is increasingly being recognized as a highly prevalent and undertreated problem. This study was conducted to determine the prevalence of vitamin D deficiency/insufficiency in hospitalized adults in northeast Tennessee. METHODS:: A prospective cohort study was conducted on 99 inpatients admitted to an internal medicine teaching service from July through October 2006 at a single private hospital in Johnson City, Tennessee. A single measurement of 25-hydroxyvitamin D was performed on all patients. RESULTS:: Of the 99 patients, 53% were vitamin D deficient or insufficient (30% deficient with a level of <20 ng/mL and 23% insufficient with a level between 20ĝ€"29.9 ng/mL). The highest frequency of deficiency was in females <50 years. CONCLUSION:: Vitamin D deficiency is highly prevalent in all age groups and in both females and males in this population. Clinicians should consider measuring the vitamin D level of all inpatients on a routine basis.

Background: Calciferol (vitamin D) is an essential nutrient that can be synthesized in the skin upon exposure to ultraviolet-B (UVB) light, or obtained through dietary and supplement sources. Traditionally known for its role in bone metabolism, vitamin D is currently described as a pleiotropic hormone with genomic and non-genomic roles in most body tissues. Clinical practice guidelines related to vitamin D are inconsistent and controversial. The purpose of this dissertation was to describe current patterns of vitamin D-related clinical care in a variety of settings, and to evaluate the impact of vitamin D supplements on the health and performance of collegiate athletes, a group with high prevalence of low vitamin D (LVD). Methods: This dissertation consists of five studies: 1) a scoping review of the health services literature related to clinical management of vitamin D; 2) a retrospective analysis of clinical care following non-indicated vitamin D testing using electronic health record (EHR) data from a regional health system; 3) a survey study to assess vitamin D-related practices among National Collegiate Athletic Association (NCAA) Division I programs; 4) an open clinical trial to evaluate the efficacy of a specific vitamin D supplement protocol in treating collegiate basketball athletes with LVD; and 5) a randomized, double-blind clinical trial to determine health and performance effects of vitamin D supplements in collegiate swimmers participating in fall season training. Results: Substantial inconsistency in vitamin D-related care was observed throughout the first three studies. Exponential increases in vitamin D testing and treatment, and associated costs, were identified in the U.S. and several other countries. A high proportion of this care was considered non-indicated (i.e., counter to professional guidelines). A lower rate of non-indicated vitamin D-related services was conducted within the health system we studied, but a cascade of low value services followed non-indicated vitamin D testing. Vitamin D testing was regularly performed by more than 65% of NCAA programs. In basketball athletes, 10 weeks of daily vitamin D3 supplements (5000 or 10,000 IU based on initial vitamin D status) improved serum 25-hydroxyvitamin D [25(OH)D], the common biomarker of vitamin D status. In swimmers, a vitamin D supplement protocol (5,000 IU vitamin D3 daily for 12 weeks) was efficacious in attenuating a seasonal decline in 25(OH)D compared with placebo. Swimmers taking vitamin D supplements also showed greater improvements in strength, power, and fat free mass. In both athlete studies, taking vitamin D supplements was associated with higher free testosterone concentration. Conclusions: The provision of evidence-based care related to vitamin D is complicated by contradictory clinical practice guidelines, resulting in inconsistent and sometimes, non-indicated care. Focused research on specific populations at high-risk for LVD can inform best practices. Our results suggest that taking vitamin D supplements is an efficacious strategy for athletes to improve 25(OH)D, especially when UVB exposure is low, and to enhance strength and power in collegiate swimmers. / Ph.D. / Vitamin D is known as the “sunshine vitamin” since it can be synthesized by the human body when exposed to specific wavelengths of ultraviolet-B (UVB) light. Some foods and dietary supplements also contain vitamin D. A relationship between vitamin D and bone health is well-established, but emerging research has also associated vitamin D status with a number of different diseases and health problems, including cancer, cardiovascular disease, autoimmune conditions, and depression. Unfortunately, this research is currently inconclusive, and healthcare providers’ professional guidelines related to vitamin D are highly variable. Thus, providing evidence-based care related to vitamin D is complicated. This dissertation consists of a series of three research studies that describe healthcare providers’ vitamin D-related care considering the uncertain landscape, and two research studies that explore the role of vitamin D in collegiate athletes. We chose athletes since a high proportion of them have deficient or insufficient vitamin D status, and because some research has shown that this low vitamin D status affects athletic performance. Results of these studies showed that vitamin D-related health services such as blood testing have increased dramatically over the past 15 years, as have costs associated with these services. Opportunities to improve consistency and quality of care were observed in multiple settings. In the athlete studies, a high rate of vitamin D deficiency and insufficiency was observed among basketball athletes, and we identified vitamin D supplement treatment protocol effective in improving vitamin D status. In addition, swimmers who took vitamin D supplements performed better on strength and conditioning tests than those who took placebo supplements. A favorable relationship between testosterone concentrations and vitamin D status was shown in both basketball athletes and swimmers. Continuing to conduct research focused on specific populations can help healthcare providers develop consistent, high quality, evidence-based care related to vitamin D.

Background: This study examined the association of 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) with postoperative medical complications and one year mortality of elderly patients sustaining a low-energy cervical hip fracture scheduled for surgery. We hypothesized that vitamin D deficiency and CRP in these patients might be associated with an increased 1-year mortality. Methods: The prospective single-center cohort study included 209 patients with a low-energy medial femoral neck fracture; 164 women aged over 50 years and 45 men aged over 60 years. Referring to 1-year mortality and postoperative medical complications multiple logistic regression analysis including 10 co-variables (age, sex, BMI, ASA, creatinine, CRP, leukocytes hemoglobin, 25(OH)D, vitamin D supplementation at follow-up) was performed. Results: Vitamin D deficiency was prevalent in 87 % of all patients. In patients with severe (<10 ng/ml) and moderate (10–20 ng/ml) vitamin D deficiency one year mortality was 29 % and 13 %, respectively, compared to 9 % in patients with > 20 ng/ml 25(OH)D levels (p =0.027). Patients with a mild (CRP 10–39.9 mg/l) or active inflammatory response (CRP ≥ 40 mg/l) showed a higher one year mortality of 33 % and 40 % compared to 16 % in patients with no (CRP < 10 mg/l) inflammatory response (p = 0.002). Multiple logistic regression analysis identified CRP (OR 1.01, 95 % CI 1.00- 1.02; p = 0.007), but not 25(OH)D (OR 0.97, 95 % CI 0.89-1.05; p = 0.425) as an independent predictor for one year mortality. 20 % of patients suffered in-hospital postoperative medical complications (i.e. pneumonia, thromboembolic events, etc.). 25(OH)D (OR 0.89, 95 % CI 0.81–0.97; p = 0.010), but not CRP (OR 1.01, 95 % CI 1.00-1.02; p = 0.139), was identified as an independent risk factor. Conclusion: In elderly patients with low-energy cervical hip fracture, 25(OH)D is independently associated with postoperative medical complications and CRP is an independent predictor of one year mortality.